Prostaglandin E.sub.1 is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula: ##STR1## and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the designation "Alprostadil USP" and from The Upjohn Company (Kalamazoo, Mich.) under the designation "Prostin VR."
Prostaglandin E.sub.1 is a vasodilator useful to maintain open blood vessels and therefore, to treat peripheral vascular disease among other ailments. While the potential benefits from transdermal delivery of prostaglandin E.sub.1 have long been recognized, prior efforts at developing a topical composition for prostaglandin delivery have not been fully successful.
In particular, there is presently no commercial source for a topical semi-solid formulation that is useful without a supporting device such as a patch, adhesive strip, and the like. For example, U.S. Pat. No. 5,380,760 to Wendel et al. is directed to a topical prostaglandin formulation that includes a pressure-sensitive, adhesive sheet of polyisobutylene.
Working alone most drugs, prostaglandin formulations included, do not sufficiently permeate the skin to provide drug concentration levels comparable to those obtained from other drug delivery routes. To overcome this problem, topical drug formulations typically include a skin penetration enhancer. Skin penetration enhancers also may be referred to as absorption enhancers, accelerants, adjuvants, solubilizers, sorption promoters, etc. Whatever the name, such agents serve to improve drug absorption across the skin. Ideal penetration enhancers not only increase drug flux across the skin, but do so without irritating, sensitizing, or damaging skin. Furthermore, ideal penetration enhancers should not affect available dosage forms (e.g. cream or gel), or cosmetic quality of the topical composition.
A wide variety of compounds have been evaluated as to their effectiveness in enhancing the rate of penetration of drugs through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).
A fully successful formulation for prostaglandin E.sub.1 has not yet been identified. Unfortunately, prostaglandin E.sub.1 is readily transformed by rearrangement and other reactions. This relative instability tends to complicate efforts at formulating composition for transdermal delivery.
The present invention addresses these problems by providing a semi-solid, separation resistant composition for relatively rapid, sustained delivery of prostaglandin E.sub.1.